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Abstract

Background

We describe the first case of systemic cat scratch disease in a patient receiving
peginterferon α-2a and ribavirin for treatment of hepatitis C. Cases of adult systemic
CSD are extremely infrequent and immunomodulatory treatment for hepatitis C has been
associated with aberrant host responses to common pathogens.

Case presentation

A 52 year old man being treated for hepatitis C presented with diffuse lymphadenopathy,
weight loss, fevers and splenic lesions. Symptoms were initially confused with adverse
effects of his regimen, delaying recognition of his infection. Diagnostic investigation,
including histopathology, microbiology and serologic parameters, confirmed that his
illness was due to disseminated cat scratch disease with Bartonella henselae.

Conclusion

Disseminated CSD is exceptionally rare in adults. We describe the first case of disseminated
cat scratch disease associated with peginterferon α and ribavirin to alert clinicians
of the need to be aware of unusual manifestations of common infections in this population.

Interferon α and ribavirin are mainstays of treatment for chronic hepatitis C, that
have been associated with aberrant immune-mediated host responses, that may resemble
adverse pharmacologic effects. In this report, we present the first description of
disseminated CSD in an adult receiving interferon 2a and ribavirin for treatment of chronic hepatitis C, in whom signs and symptoms
were initially confused with adverse effects of medications. We offer our experience
to alert clinicians of the need for awareness of unusual manifestations of commons
infections in this population.

Case Presentation

A 52-year-old male with a history of hepatitis C, genotype 1b, was nearing completion
of a one-year course of treatment with pegylated interferon 2a (180 ug subcutaneously each week) and ribavirin (1200 mg orally each day). His
initial hepatitis C viral RNA had declined from 2.2 × 106 IU/ml at onset of treatment, to <65 IU/ml by six months, and remained undetectable
thereafter. Toward the end of his course of treatment, he developed fatigue, malaise,
drenching night sweats, intermittent fever and chills. On the last visit for hepatitis
C treatment, axillary and cervical lymphadenopathy was noticed. His symptoms were
initially attributed to adverse effects of interferon α, prompting premature discontinuation
of treatment after 10.5 months. One month after onset of symptoms, he presented to
a nearby hospital for further workup.

He was transferred to the Buffalo VA Western New York Healthcare System with complaints
of malaise and left sided mid back pain. He had a documented weight loss of 40 lbs
over the previous year. He appeared chronically ill and fatigued. He had a temperature
of 101°F and a heart rate of 105 beats per minute. Generalized lymphadenopathy was
noted, including cervical, axillary, inguinal and right epitrochlear lymph nodes.
The nodes were 1–2 cm wide, firm, movable and nontender. He had left sided abdominal
fullness and mild tenderness, but no guarding or rebound. The remainder of his examination
was noncontributory.

Figure 1. Cross sectional cut of CT scan of abdomen at the time of clinical presentation. Multiple
hypoechoic densities are present in the spleen (arrows).

Initial clinical suspicion included lymphoma and he underwent a lymph node biopsy.
Further history revealed exposure to numerous cats. He frequented a neighbor who had
6–9 cats, including kittens, with which the patient had played, and from whom he received
numerous scratches. Serologic studies were sent for antibodies to Bartonella, Chlamydia,
Toxoplasma and Brucella. He was given ibuprofen for symptomatic relief.

Over the next 3–4 days, the patient defervesced and improved symptomatically on ibuprofen
alone. By the eighth day, serum antibody titers (IgG and IgM) for Bartonella henselae were reported as >1:16,384. He continued to improve without further treatment. Six
months later he was doing well and had regained 25 lbs of weight. An abdominal CT
scan revealed complete resolution of splenic lesions.

Conclusion

This is the first reported case of systemic CSD with generalized lymphadenopathy and
splenic involvement in an adult associated with immunomodulatory treatment for hepatitis
C. In our patient, the diagnosis of CSD was established by: 1) history of exposure
to cats, 2) obtaining sterile pus from a lymph node with no growth on routine cultures,
3) lymph node biopsy displaying classic findings of necrotizing stellate granulomata
with microabscesses, and 4) an extremely high titer serum antibody response to B. henselae.

Cat scratch disease was first described in 1950 [5], although manifestations that constitute the disease have been known for over 100
years. Typically lesions may appear at the site of a cat scratch, often from a young
kitten, as a papule, pustule or vesicle, followed by fever, regional lymphadenopathy
and occasional systemic symptoms. Illness is usually self-limited, resolving in 2–3
months with no treatment. Atypical signs and symptoms occur most often in children
and include Parinaud's oculoglandular syndrome (conjunctivitis, conjunctival granulomata
with preauricular lymphadenopathy), encephalitis, myelitis, hepatosplenic disease
and dissemination [6,7]. Rarely, splenic CSD may require splenectomy [8,9]. The clinical resemblance to lymphoma, of splenic abscesses in disseminated CSD such
as our patient presented with, has been described [10].

Laboratory diagnosis of CSD includes appropriate histological findings and detection
of serum antibodies to B. henselae by enzyme immunoassay, which has a specificity of up to 95% and sensitivity of 83–95%,
when IgM titer is greater than 1:250 [11,12]. PCR assay of tissue or blood, although not employed routinely, may have high sensitivity
and specificity [13]. PCR techniques have been applied to immunofluorescent detection of B. henselae in tissue sections. Although sensitivity of this method has been variable, high specificity
of positive samples may be of value when the diagnosis is in question [14,15]. Recent reports of high sensitivity of immunohistochemistry with monoclonal antibodies
to B. henselae, tested on a limited numbers of tissue samples, suggest potential future value [16]. Although well characterized, these techniques are not universally employed [17].

While the specific factors that permit dissemination of CSD are not known, clinical
experience confirms that the host response to B. henselae contributes to the manifestation of disease. This is illustrated by the experience
with B. henselae in AIDS patients, where the same pathogen that causes self-limited regional lymphadenopathy
in immunocompetent hosts, causes bacillary angiomatosis and peliosis hepatis [18]. However, other immunodeficient states, such as chronic lymphocytic leukemia and
T cell lymphoma, can also trigger dissemination of CSD [19,20]. In fact, the immunomodulatory effects of co-infection with EBV may have been responsible
for one case of disseminated CSD [21].

Although the impact of interferon α and ribavirin on host immune response has had
limited characterization, aberrant host responses associated with this regimen are
well known, including immune-mediated Graves' disease and sarcoidosis [22]. Although advanced forms of infection, including visceral leishmaniasis [23] have been reported with interferon-α and ribavirin therapy, a major focus of infectious
complications has been associated with drug induced neutropenia [24]. This was clearly not the case in our patient. Interferon α exerts biological activities
by binding to cell membranes receptors, initiating numerous cellular events, including
upregulation of Th1 cells and modulation of immunological activities of macrophages
and lymphocytes [25]. While the precise clinical relevance of these events is not known, it is difficult
to ignore the temporal relationship between administration of this regimen and onset
of disease in our patient, most likely due to immunomodulatory factors, aside from
neutropenia, affected by this regimen. In addition, adverse effects of therapy, including
flu-like symptoms, fatigue (47–64%), fever (39–46%), and rigors (35%), were also present
at the onset of our patient's illness, resulting in delayed recognition of his infection
[26].

The success and increasing utilization of interferon α and ribavirin for treatment
of hepatitis C will undoubtedly reveal a greater number of interferon-related side
effects in the future. We offer the experience of our patient to alert clinicians
of the need to be aware of aberrant presentations of infections in this population.

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

Both authors (ZB and CSB) contributed equally to the research and design of this manuscript.

Acknowledgements

The authors are grateful to Timothy F. Murphy, M.D., for critical reading of this
manuscript. Written consent was obtained from the patient's relative for publication
of this case report. This study was accomplished with support from the Department
of Veteran's Affairs.